Increased Survival and Function of SOD1 Mice After Glial Cell-Derived Neurotrophic Factor Gene Therapy

Abstract

Amyotrophic lateral sclerosis (ALS) is caused by a progressive degeneration of motor neurons. The cause of sporadic ALS is not known, but 1-2% of all cases are familial and caused by mutations in the copper-zinc superoxide dismutase (SOD1) gene. Transgenic SOD1 mice serve as a transgenic mouse model for these cases. Glial cell-derived neurotrophic factor (GDNF) has a potent trophic effect on motor neurons. Clinical trials in which growth factors have been systemically administered to ALS patients have not been effective, owing in part to the short half-life of these factors and their low concentrations at target sites. Gene transfer of therapeutic factors to motor neurons and/or their target cells, such as muscle, may overcome these problems. Previously, we and others have shown that intramuscularly administered adenovirus vector (AVR) results in foreign gene expression not only in muscle cells, but also in relevant motor neurons in the spinal cord, because of retrograde axonal transport. In this study we utilized an AVR to introduce GDNF into muscles of neonatal SOD1 mice. We showed that AVR-mediated GDNF expression delayed the onset of disease by 7 +/- 8 days (mean +/- SD), prolonged survival by 17 +/- 10 days, and delayed the decline in motor functions (as determined on a rotating rod) by 7-14 days. These results demonstrate that gene delivery to muscle and motor neurons has the potential to treat devastating neurodegenerative diseases such as ALS.

Adenoviral clostridial light chain gene-based synaptic inhibition through neuronal synaptobrevin elimination

“…Adult female SpragueDawley rats (Harlan, Indianapolis, IN, USA), weighing 150-250 g, were served as experimental subjects. Using standard techniques, 48 rats were randomly assigned to four groups and trained to run on the Economex rotarod apparatus (Columbus Instruments, Columbus, OH, USA) for 1 week prior to surgery. The day prior to surgery, locomotion was assessed on the 21-point BBB scale.…”

“…The Economex rotarod apparatus has previously been utilized to efficiently assay the behavioral impact of progressive MN disease. 48 Performance on the rotarod tests both forelimb and hindlimb function as well as balance. Following establishment of the baseline motor performance at 5 r.p.m.…”

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

“…Previous studies in animal models of motor neuron disease (SOD1, wobbler, progressive motor neuronopathy, spinal muscle atrophy) have shown that therapeutic benefits can be achieved via adenovirus-, lentivirus-, herpes simplex virus-and adeno-associated virus (AAV)-based delivery of genes such as mutant SOD1-targeted RNAi [48,49], VEGF [6], NT-3 [28], CNTF [2], GDNF [1,58], IGF-1 [34], Bcl-2 [5] and cardiotrophin-1 [13]. Clinical translation with some of these proteins has not yielded similar efficacy in human ALS patients [12,25,26,36]; however, trials have mostly involved systemic injection of protein, not viral vector-based gene delivery.…”

Glycinergic and GABAergic Synaptic Activity Differentially Regulate Motoneuron Survival and Skeletal Muscle Innervation

“…During embryonic development, approximately half of the motoneurons generated undergo programmed cell death (PCD) (Oppenheim, 1991). Motoneuron survival and differentiation depend on trophic factors secreted from target muscle fibers and Schwann cells surrounding motor axons (Bordet et al, 2001;Acsadi et al, 2002;Wang et al, 2002;Lu et al, 2003). Reductions in skeletal muscle activity improve the access of a motoneuron to target-derived trophic factors by increasing the extent to which motor axons branch and form neuromuscular synapses (Oppenheim et al, 2000b;Millecamps et al, 2001Millecamps et al, , 2002.…”